Hyperammonemia causes glial swelling, increased intracranial pressure, impaired cerebrovascular responses to CO2, and altered brain electrical function. This proposal examines the hypothesis that glial swelling plays a prominent role in the aforementioned physiological abnormalities found in hyperammonemic states. It is further proposed that glial swelling is a consequence of the osmotic effect of the accumulation of intracellular free glutamine in glia, where glutamine synthetase activity is high. Glial swelling and glutamine accumulation may be responsible for physiological abnormalities by one or both of two potential mechanisms. By virtue of its relationship to the microcirculation, glial swelling may directly affect control of the vasculature. By virtue of its role in the regulation of the extracellular ionic environment, glial abnormalities may affect electrical activity and vascular responsivity. To test these hypotheses, a series of experiments are designed to compare the consequences of hyperammonemia in control animals with those pretreated with methionine sulfoximine (MSO), a potent glutamine synthetase inhibitor; this will permit evaluation of hyperammonemia in the presence and absence of brain glutamine accumulation. Specifically, we will determine if the increase in brain water and intracranial pressure, and the impaired cerebrovascular reactivity and brain electrical function are prevented during hyperammonemia when animals are pretreated with MSO. The gradual development of moderate hyperammonemia over a 72 hour period will be investigated by intraperitoneal infusion of urease in dogs. By evaluating the cerebrovascular responses to hypercapnia, hypocapnia, hypoxia, and increases and decreases in perfusion pressure, we will demonstrate whether hyperammonemia produces a generalized depression of vascular reactivity or if the depression is specific for a particular vasodilator or vasoconstrictor stimulus. By measuring pial arteriole diameter, we will show whether extraparenchymal vessels not surrounded by glia lose reactivity in the same fashion as the total cerebrovascular network. We will then demonstrate if alterations in extracellular fluid composition are responsible for altered reactivity. This proposal will incorporate existing biochemical evidence into an integrative physiological explanation of the cerebrovascular abnormalities which occur in experimental and clinical hyperammonemic states.